Patients with autoimmune diseases are categorized by clinical manifestations and simple laboratory values. However recent mechanistic investigations, and experience with directed biological therapies, have demonstrated that these autoimmune disease categories are very heterogeneous. Despite this apparent heterogeneity most, if not all, autoimmune diseases share a common theme. They arise from failures in self tolerance. Therefore, we propose to establish the University of Chicago Autoimmunity Center of Excellence (UCACE) with the purpose of studying and manipulating lymphocyte tolerance in patients with diverse autoimmune diseases including systemic lupus erythematosus (SLE), myasthenia gravis (MG) and inflammatory bowel disease (IBD). Central to this effort will be the establishment of a core facility, the Autoimmune Lymphocyte Repertoire Core (ALRC) that will enable investigators from multiple disciplines to assess the evolution of humoral autoimmunity in rare human lymphocyte subpopulations. The singular research focus of the UCACE will be complemented by an innovative clinical trials program, and administrative structure, that will facilitate mechanistic studies in patients receiving novel lymphocyte-directed therapies. Understanding how lymphocyte tolerance is breached in different autoimmune diseases will reveal commonalities and differences that will enable the development of new biomarkers and novel therapeutics. RELEVANCE: Autoimmunity is manifest in a myriad of diseases that preferentially afflict younger patients who are often pursing careers and raising families. The total burden of autoimmune diseases on society is substantial. The focus of the current application is the pathogenesis of human autoimmunity. It is anticipated that these studies will contribute to the development of new therapies to treat those afflicted with autoimmune diseases. Clinical Component: Clinical Component of University of Chicago Autoimmunity Center of Excellence (Hanauer, S) CLINICAL COMPONENT DESCRIPTION (Provided by applicant): The University of Chicago clinical, translational and basic science programs form an interactive network of research and clinical resources focused on understanding and treating human disease. Integration of clinical and basic science missions is ensured by a common administrative structure in which both the University of Chicago Medical Center and Biological Sciences Division (BSD) are under a single Dean/CEO Office that oversees and defines the priorities of both enterprises. Integration is then reinforced by a system of common core facilities, multidisciplinary research institutes, centers and programs and, ultimately, by faculty who broadly collaborate in both the research and clinical activities of the University. The University of Chicago Autoimmunity Center of Excellence proposes to establish a Clinical Trials Program (UCACE-CTP) that will capitalize on this established clinical-academic structure to create and conduct clinical trials in autoimmunity that are tightly coupled to mechanistic studies. Successful models for accomplishment of this aim are already well established within the participating clinical sections and departments of the UCACE. Therefore, the primary goal of the UCACE-CTP will be to standardize procedures for clinical trials management across clinical center participants and to provide a common platform integrating efforts within the UCACE and ACE networks. Finally, the UCACE-CTP will develop a system of mentorship and peer review that will encourage clinical and translational investigators to develop novel therapeutic and mechanistic studies on patients with autoimmune disease. RELEVANCE: The purpose of the University of Chicago Autoimmunity Center of Excellence (UCACE) Clinical Trials Program is to promote clinical trials in autoimmunity that are tightly coupled to insightful mechanistic studies. This goal is highly relevant to developing new therapies for patients with autoimmunity.